Aminocarbonyl-substituted 8-N-benzimidazoles, methods for their preparation and their use in pharmaceutical compositions

ABSTRACT

The present invention comprises the use of amino-carbonyl-substituted 8-N-benzimidazoles compounds of formula I 
                         
wherein R3, R4-R5, R11 and R20-R21 are hereinafter defined which display a therapeutically utilizable blood sugar-lowering action. These compounds are intended to be particularly suitable in the treatment of diabetes, carbohydrate and lipid metabolic disorders and other blood sugar complications.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/EP2006/002056 filed on Mar. 7, 2006 which is incorporated hereinby reference in its entirety which also claims the benefit of priorityof German patent application Ser. No. 10/2005012873.2 filed on Mar. 19,2005.

FIELD OF THE INVENTION

The present invention relates generally to pharmaceutical compounds andcompositions comprising them for the treatment of metabolic blood serumdisorders and the physiological manifestations thereof. Morespecifically, the present invention relates to pharmaceutical compoundsand compositions comprising them for the treatment of metabolic bloodglucose disorders such as diabetes, hypoglycemia, hyperglycemia,hyperlipidemia, hypercholesterolemia and the like. More specifically,the present invention relates to amino-substituted 8-N-benzimidazolesand derivatives thereof for the treatment of blood glucose disorders.

BACKGROUND OF THE INVENTION

The present invention comprises the use of amino-substituted8-N-benzimidazoles and the physiologically compatible salts thereof forproducing a pharmaceutical composition for the treatment of blood sugardisorders. These compounds are particularly useful in the reduction ofblood sugar and, more specifically, in the therapeutic treatment ofdiabetes. The use of related or similar compounds has been known anddescribed in the prior art as follows. EP 1069124 describes2-benzimidazolylamines as ORL-1 receptor agonists. WO 97/12615 describesbenzimidazole derivatives as 15-LO inhibitors and WO 02/04425 describesstructurally similar virus polymerase inhibitors. 1069124 describes2-benzimidazolylamines as ORL-1 receptor agonists CA 2,148,053 describesstructurally similar tachykinin receptor antagonists while WO 02/46168describes structurally similar estrogen receptor ligands

SUMMARY OF THE INVENTION

The present invention comprises the use of amino-substituted8-N-benzimidazoles compounds of formula I

wherein R3, R4-R5, R11 and R20-R21 are hereinafter defined which displaya therapeutically utilizable blood sugar-lowering action. Thesecompounds are intended to be particularly suitable in the treatment ofdiabetes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises a class of compounds which display atherapeutically utilizable blood sugar-lowering action. These compoundsshould be particularly suitable for treating diabetes. Morespecifically, the present invention comprises compounds of formula I asset forth hereinbelow:

in which

-   R20 is selected from the group consisting of H, (C₁-C₁₀)-alkyl,    (C₃-C₁₀)-cycloalkyl, (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl,    (C₆-C₁₀)-aryl, heterocycle, (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-heterocycle and S(O)₂-aryl, where the    alkyl, cycloalkyl, alkenyl, alkynyl, alkylene, aryl and the    heterocycle radicals may each be mono- or polysubstituted by F, Cl,    Br, I, CN, NO₂, SH, OH, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or    S—(C₁-C₆)-alkyl;-   R21 is selected from the group consisting of (C₁-C₃)-alkyl wherein    (C₁-C₃)-alkyl is mono- or polysubstituted by CN, NO₂, SH, OH,    (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl; (C₄-C₆)-alkyl    where (C₄-C₆)-alkyl is mono- or polysubstituted by F, Cl, Br, I, CN,    NO₂, SH, OH, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl;    (C₇-C₁₀)-alkyl where (C₇-C₁₀)-alkyl may be mono- or polysubstituted    by F, Cl, Br, I, CN, NO₂, SH, OH, CF₃, O—(C₁-C₆)-alkyl or    S—(C₁-C₆)-alkyl; (C₃-C₁₀)-cycloalkyl, (C₂-C₁₀)-alkenyl, (C₂-C₁₀)    alkynyl, (C₆-C₁₀)-aryl, heterocycle, (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-heterocycle and S(O)₂-aryl, wherein the    alkyl, cycloalkyl, alkenyl, alkynyl, alkylene, aryl and heterocycle    radicals may be mono- or polysubstituted by F, Cl, Br, I, CN, NO₂,    SH, OH, CF₃, O—(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl;-   R3 is selected from the group consisting of (C₂-C₁₀)-alkyl,    (C₃-C₁₀)-cycloalkyl, (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl,    (C₆-C₁₀)-aryl or heterocycle, where the alkyl, cycloalkyl, alkenyl,    alkynyl, aryl and heterocycle radicals may be mono- or    polysubstituted by F, Cl, Br, I, CN, NO₂, SH, OH, (C₁-C₆)-alkyl,    —CF₃, —OCF₃, —SCF₃, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, OR7,    OP(O)(OR7)₂, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8,    OCONR7R8, (C₁-C₆)-alkylene-OR7, (C₁-C₆)-alkylene-NR7R8,    (C₁-C₆)-alkylene-NR7S(O)₂R7, (C₁-C₆)-alkylene-SR7,    (C₁-C₆)-alkylene-S(O)R7, (C₁-C₆)-alkylene-S(O)₂R7,    (C₁-C₆)-alkylene-S(O)₂NR7R8, (C₁-C₆)-alkylene-COR7,    (C₁-C₆)-alkylene-COOR7, (C₁-C₆)-alkylene-CONR7R8, SR7, S(O)R7,    S(O)₂R7, S(O)₂NR7R8, NR7S(O)₂R7,    (C₁-C₆)-alkylene-(C₃-C₁₀)-cycloalkyl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, (C₁-C₆)-alkylene-heterocycle,    (C₃-C₁₀)-cycloalkyl, (C₆-C₁₀)-aryl and heterocycle;-   R7 and R8 are each independently selected from the group consisting    of H, (C₁-C₆)-alkyl, —CF₃, (C₃-C₁₀)-cycloalkyl, (C₆-C₁₀)-aryl,    heterocycle, (C₁-C₆)-alkylene-CONR9R10, CONR9R10,    (C₁-C₆)-alkylene-COOR9, COOR9, COR9, (C₁-C₆)-alkylene-COR9,    (C₁-C₆)-alkylene-OR9, (C₁-C₆)-alkylene-NR9R10, (C₁-C₆)-alkylene-SR9,    (C₁-C₆)-alkylene-S(O)R9, (C₁-C₆)-alkylene-S(O)₂R9, S(O)R9, S(O)₂R9,    (C₁-C₄)-alkylene-(C₆-C₁₀)-aryl and (C₁-C₄)-alkylene-heterocycle;-   R9 and R10 are each independently is selected from the group    consisting of H, (C₁-C₆)-alkyl, (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl,    —(C₆-C₁₀)-aryl, heterocycle or (C₁-C₆)-alkylene-heterocycle;-   R4 and R5 are each independently is selected from the group    consisting of H, (C₁-C₆)-alkyl or (C₃-C₈)-cycloalkyl, where    (C₁-C₆)-alkyl or (C₃-C₈)-cycloalkyl may be substituted by F, Cl, Br,    I, CN, aryl, heterocycle, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,    OH, O(C₁-C₆)-alkyl, O-aryl, O-heteroaryl, S(C₁-C₆)-alkyl,    S(O)(C₁-C₆)-alkyl or S(O)₂(C₁-C₆)-alkyl, where these alkyl groups    may in turn be substituted by F, Cl, Br or I;-   R11 is selected from the group consisting of F, Cl, Br, I,    (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, NH₂, NH(C₁-C₆)-alkyl,    NH(C₃-C₇)-cycloalkyl, N((C₁-C₆)-alkyl)₂ or O—(C₁-C₆)-alkyl, where    the alkyl groups may be mono- and polysubstituted by F, Cl, Br or I;    n is 0, 1 or 2;    excluding those compounds in which R20 and R21 are simultaneously    defined as an unsubstituted phenyl or unsubstituted benzyl, and R3    is a substituted or unsubstituted (C₂-C₁₀)-alkyl,    (C₃-C₁₀)-cycloalkyl, (C₆-C₁₀)-aryl or heterocycle;    and the pharmaceutically acceptable salts thereof.

Preferably, the present invention comprises compounds of formula I inwhich one or more of the R-group substituents are each defined asfollows:

-   R20 is selected from the group consisting of H, (C₁-C₁₀)-alkyl,    (C₃-C₁₀)-cycloalkyl, (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl,    (C₆-C₁₀)-aryl, heterocycle, (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-heterocycle or S(O)₂-aryl, wherein the    alkyl, cycloalkyl, alkenyl, alkynyl, alkylene, aryl and heterocycle    groups may each be mono- or polysubstituted by F, Cl, Br, I, CN,    NO₂, SH, OH, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl;-   R21 is selected from the group consisting of (C₁-C₃)-alkyl where    (C₁-C₃)-alkyl is mono- or polysubstituted by CN, NO₂, SH, OH,    (C₁-C₆)-alkyl, O—(C₂-C₆)-alkyl or S—(C₁-C₆)-alkyl; (C₄-C₆)-alkyl    wherein (C₄-C₆)-alkyl is mono- or polysubstituted by F, Cl, Br, I,    CN, NO₂, SH, OH, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or    S—(C₁-C₆)-alkyl; (C₇-C₁₀)-alkyl wherein (C₇-C₁₀)-alkyl may be mono-    or polysubstituted by F, Cl, Br, I, CN, NO₂, SH, OH, CF₃,    (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl;    (C₃-C₁₀)-cycloalkyl, (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl,    (C₆-C₁₀)-aryl, heterocycle, (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-heterocycle or S(O)₂-aryl, wherein the    alkyl, cycloalkyl, alkenyl, alkynyl, alkylene, aryl and heterocycle    radicals may be mono- or polysubstituted by F, Cl, Br, I, CN, NO₂,    SH, OH, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl and S—(C₁-C₆)-alkyl;-   R3 is selected from the group consisting of (C₂-C₁₀)-alkenyl,    (C₂-C₁₀)-alkynyl, wherein the alkenyl and alkynyl radicals may be    mono- or polysubstituted by F, Cl, Br, I, CN, NO₂, SH, OH,    (C₁-C₆)-alkyl, —CF₃, —OCF₃, —SCF₃, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,    OR7, OP(O)(OR7)₂, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7,    CONR7R8, OCONR7R8, (C₁-C₆)-alkylene-OR7, (C₁-C₆)-alkylene-NR7R8,    (C₁-C₆)-alkylene-NR7S(O)₂R7, (C₁-C₆)-alkylene-SR7,    (C₁-C₆)-alkylene-S(O)R7, (C₁-C₆)-alkylene-S(O)₂R7,    (C₁-C₆)-alkylene-S(O)₂NR7R8, (C₁-C₆)-alkylene-COR7,    (C₁-C₆)-alkylene-COOR7, (C₁-C₆)-alkylene-CONR7R8, SR7, S(O)R7,    S(O)₂R7, S(O)₂NR7R8, NR7S(O)₂R7,    (C₁-C₆)-alkylene-(C₃-C₁₀)-cycloalkyl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, (C₁-C₆)-alkylene-heterocycle,    (C₃-C₁₀)-cycloalkyl, (C₆-C₁₀)-aryl and heterocycle;-   R7 and R8 are each independently selected from the group consisting    of H, (C₁-C₆)-alkyl, —CF₃, (C₃-C₁₀)-cycloalkyl, (C₆-C₁₀)-aryl,    heterocycle, (C₁-C₆)-alkylene-CONR9R10, CONR9R10,    (C₁-C₆)-alkylene-COOR9, COOR9, COR9, (C₁-C₆)-alkylene-COR9,    (C₁-C₆)-alkylene-OR9, (C₁-C₆)-alkylene-NR9R10, (C₁-C₆)-alkylene-SR9,    (C₁-C₆)-alkylene-S(O)R9, (C₁-C₆)-alkylene-S(O)₂R9, S(O)R9, S(O)₂R9,    (C₁-C₄)-alkylene-(C₆-C₁₀)-aryl and (C₁-C₄)-alkylene-heterocycle;-   R9 and R10 are each independently selected from the group consisting    of H, (C₁-C₆)-alkyl, (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, —(C₆-C₁₀)-aryl,    heterocycle and (C₁-C₆)-alkylene-heterocycle;-   R4 and R5 are each independently H, (C₁-C₆)-alkyl or    (C₃-C₈)-cycloalkyl, where (C₁-C₆)-alkyl or (C₃-C₈)-cycloalkyl may be    substituted by F, Cl, Br, I, CN, aryl, heterocycle, NH₂,    NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, OH, O(C₁-C₆)-alkyl, O-aryl,    O-heteroaryl, S(C₁-C₆)-alkyl, S(O)(C₁-C₆)-alkyl or    S(O)₂(C₁-C₆)-alkyl, where these alkyl groups may in turn be    substituted by F, Cl, Br or I;-   R11 is F, Cl, Br, I, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, NH₂,    NH(C₁-C₆)-alkyl, NH(C₃-C₇)-cycloalkyl, N((C₁-C₆)-alkyl)₂ and    O—(C₁-C₆)-alkyl, where the alkyl groups may be mono- or    polysubstituted by F, Cl, Br or I;    n is 0, 1 or 2;    and the pharmaceutically acceptable salts thereof.

More preferably, compounds of the present invention are those accordingto formula I in which:

-   R20 is H;-   R21 is selected from the group consisting of (C₆-C₁₀)-aryl and    (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl where the aryl radicals may be mono-    or polysubstituted by F, Cl, Br, I, CN, NO₂, SH, OH, CF₃,    (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl;-   R3 is selected from the group consisting of (C₂-C₁₀)-alkenyl;-   R4 and R5 are each independently selected from the group consisting    of H, (C₁-C₆)-alkyl or (C₃-C₈)-cycloalkyl, where (C₁-C₆)-alkyl or    (C₃-C₈)-cycloalkyl may be substituted by F, Cl, Br, I, CN, aryl,    heterocycle, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, OH,    O(C₁-C₆)-alkyl, O-aryl, O-heteroaryl, S(C₁-C₆)-alkyl,    S(O)(C₁-C₆)-alkyl and S(O)₂(C₁-C₆)-alkyl, where these alkyl groups    in turn may be substituted by F, Cl, Br or I;    n is 0    and the pharmaceutically acceptable salts thereof.

More preferably, compounds of the present invention comprise thosecompounds of formula I in which;

R20 is H;

R21 selected from the group consisting of (C₆-C₁₀)-aryl or(C₁-C₆)-alkylene-(C₆-C₁₀)-aryl wherein the aryl substituents may bemono- or polysubstituted by F, Cl, Br, I, CN, NO₂, SH, OH, CF₃,(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl;

R3 is selected from the group consisting of (C₂-C₁₀)-alkenyl;

R4 and R5 are each H;

n is 0;

and the pharmaceutically acceptable salts thereof.

Notwithstanding the disclosure above, the present invention alsocomprises compounds of formula I including their racemates, racemicmixtures, pure enantiomers, and also to their diastereomers and mixturesthereof.

When the R-groups or substituents can occur more than once in thecompounds of formula I, they may all each independently have thedefinitions specified and be the same or different.

Owing to their higher water solubility, pharmaceutically acceptablesalts are particularly suitable for medical applications as compared totheir base compounds. These salts must have a pharmaceuticallyacceptable anion or cation. Suitable pharmaceutically acceptable acidaddition salts of the inventive compounds are salts of inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid,metaphosphoric acid, nitric acid and sulfuric acid, and organic acids,for example acetic acid, benzenesulfonic acid, benzoic acid, citricacid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid,isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid,methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaricacid. Suitable pharmaceutically acceptable basic salts are ammoniumsalts, alkali metal salts (such as sodium and potassium salts) andalkaline earth metal salts (such as magnesium and calcium salts) andsalts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion, for exampletrifluoroacetate, are likewise included in the scope of the invention asuseful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for the use in non-therapeutic,for example in vitro, applications.

The term “physiologically functional derivative” used here refers to anyphysiologically compatible derivative of an inventive compound of theformula I, for example an ester which, on administration to a mammal,for example the human, is capable (directly or indirectly) of forming acompound of the formula I or an active metabolite thereof.

The physiologically functional derivatives also include prodrugs of theinventive compounds. Such prodrugs can be metabolized in vivo resultingin the active form of the compounds of the present invention. Theseprodrugs may or may not themselves be active.

The inventive compounds may also be present in various polymorphicforms, for example as amorphous and crystalline polymorphic forms. Allpolymorphic forms of the compounds of the present invention are includedwithin the scope and claims of the present invention.

Hereinafter, all references to “compound(s) of formula (I)” relate tocompound(s) of the formula I as described above, as well as their salts,solvates and physiologically functional derivatives as described herein.

An alkyl group for the purposes of this application is a straight-chainor branched hydrocarbon chain having one or more carbons, for examplemethyl, ethyl, isopropyl, tert-butyl, hexyl.

The alkyl radicals may be mono- or polysubstituted by suitable groups,for example:

F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, cycloalkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-aryl,O—CO—(C₁-C₆)-heterocycle; PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl,SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-aryl,S—(CH₂)_(n)-heterocycle, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-aryl,SO—(CH₂)_(n)-heterocycle, SO₂—(C₁-C₆)-alkyl, SO₂—(CH₂)_(n)-aryl,SO₂—(CH₂)_(n)-heterocycle, SO₂—NH(CH₂)_(n)-aryl,SO₂—NH(CH₂)_(n)-heterocycle, SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-aryl,SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-heterocycle, SO₂—N((CH₂)_(n)-aryl)₂,SO₂—N((CH₂)_(n)-heterocycle)₂ where n may be 0-6 and the aryl radical orheterocyclic radical may be up to disubstituted by F, Cl, Br, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or NH₂;C(═NH)(NH₂), NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,NH—CO—(C₁-C₆)-alkyl, NH—COO—(C₁-C₆)-alkyl, NH—CO-aryl,NH—CO-heterocycle, NH—COO-aryl, NH—COO-heterocycle,NH—CO—NH—(C₁-C₆)-alkyl, NH—CO—NH-aryl, NH—CO—NH-heterocycle,N((C₁-C₆)-alkyl)-CO—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)-COO—(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)-CO-aryl, N((C₁-C₆)-alkyl)-CO-heterocycle,N((C₁-C₆)-alkyl)-COO-aryl, N((C₁-C₆)-alkyl)-COO-heterocycle,N((C₁-C₆)-alkyl)-CO—NH—(C₁-C₆)-alkyl), N((C₁-C₆)-alkyl)-CO—NH-aryl,N((C₁-C₆)-alkyl)-CO—NH-heterocycle,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)₂,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-aryl,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-heterocycle,N((C₁-C₆)-alkyl)-CO—N-(aryl)₂, N((C₁-C₆)-alkyl)-CO—N-(heterocycle)₂,N(aryl)-CO—(C₁-C₆)-alkyl, N(heterocycle)-CO—(C₁-C₆)-alkyl,N(aryl)-COO—(C₁-C₆)-alkyl, N(heterocycle)-COO—(C₁-C₆)-alkyl,N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl,N(heterocycle)-COO-aryl, N(aryl)-CO—NH—(C₁-C₆)-alkyl),N(heterocycle)-CO—NH—(C₁-C₆)-alkyl), N(aryl)-CO—NH-aryl,N(heterocycle)-CO—NH-aryl, N(aryl)-CO—N((C₁-C₆)-alkyl)₂,N(heterocycle)-CO—N((C₁-C₆)-alkyl)₂, N(aryl)-CO—N((C₁-C₆)-alkyl)-aryl,N(heterocycle)-CO—N((C₁-C₆)-alkyl)-aryl, N(aryl)-CO—N-(aryl)₂,N(heterocycle)-CO—N-(aryl)₂, aryl, O—(CH₂)_(n)-aryl andO—(CH₂)_(n)-heterocycle, where n may be 0-6, where the aryl radical orheterocyclic radical may be mono- to trisubstituted by F, Cl, Br, I, OH,CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl orCONH₂.

An alkenyl group or substituent for the purposes of this application isa straight-chain or branched hydrocarbon chain having two or morecarbons and one or more double bonds, for example vinyl, allyl,pentenyl, 2-methyl-but-2-en-4-yl.

The alkenyl groups may be mono- or polysubstituted by additionalsubstituents for example:

F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, cycloalkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-aryl,O—CO—(C₁-C₆)-heterocycle; PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl,SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-aryl,S—(CH₂)_(n)-heterocycle, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-aryl,SO—(CH₂)_(n)-heterocycle, SO₂—(C₁-C₆)-alkyl, SO₂—(CH₂)_(n)-aryl,SO₂—(CH₂)_(n)-heterocycle, SO₂—NH(CH₂)_(n)-aryl,SO₂—NH(CH₂)_(n)-heterocycle, SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-aryl,SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-heterocycle, SO₂—N((CH₂)_(n)-aryl)₂,SO₂—N((CH₂)_(n)-heterocycle)₂ where n may be 0-6 and the aryl radical orheterocyclic radical may be up to disubstituted by F, Cl, Br, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or NH₂;C(═NH)(NH₂), NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,NH—CO—(C₁-C₆)-alkyl, NH—COO—(C₁-C₆)-alkyl, NH—CO-aryl,NH—CO-heterocycle, NH—COO-aryl, NH—COO-heterocycle,NH—CO—NH—(C₁-C₆)-alkyl, NH—CO—NH-aryl, NH—CO—NH-heterocycle,N((C₁-C₆)-alkyl)-CO—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)-COO—(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)-CO-aryl, N((C₁-C₆)-alkyl)-CO-heterocycle,N((C₁-C₆)-alkyl)-COO-aryl, N((C₁-C₆)-alkyl)-COO-heterocycle,N((C₁-C₆)-alkyl)-CO—NH—(C₁-C₆)-alkyl), N((C₁-C₆)-alkyl)-CO—NH-aryl,N((C₁-C₆)-alkyl)-CO—NH-heterocycle,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)₂,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-aryl,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-heterocycle,N((C₁-C₆)-alkyl)-CO—N-(aryl)₂, N((C₁-C₆)-alkyl)-CO—N-(heterocycle)₂,N(aryl)-CO—(C₁-C₆)-alkyl, N(heterocycle)-CO—(C₁-C₆)-alkyl,N(aryl)-COO—(C₁-C₆)-alkyl, N(heterocycle)-COO—(C₁-C₆)-alkyl,N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl,N(heterocycle)-COO-aryl, N(aryl)-CO—NH—(C₁-C₆)-alkyl),N(heterocycle)-CO—NH—(C₁-C₆)-alkyl), N(aryl)-CO—NH-aryl,N(heterocycle)-CO—NH-aryl, N(aryl)-CO—N((C₁-C₆)-alkyl)₂,N(heterocycle)-CO—N((C₁-C₆)-alkyl)₂, N(aryl)-CO—N((C₁-C₆)-alkyl)-aryl,N(heterocycle)-CO—N((C₁-C₆)-alkyl)-aryl, N(aryl)-CO—N-(aryl)₂,N(heterocycle)-CO—N-(aryl)₂, aryl, O—(CH₂)_(r)-aryl andO—(CH₂)_(n)-heterocycle, where n may be 0-6, where the aryl radical orheterocyclic radical may be mono- to trisubstituted by F, Cl, Br, I, OH,CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl orCONH₂.

An alkynyl group for the purposes of this application is understood tomean a straight-chain or branched hydrocarbon chain having two or morecarbons and one or more triple bonds, for example ethynyl, propynyl,butynyl, hexynyl.

The alkynyl radicals may be mono- or polysubstituted by suitable groups,for example:

F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, cycloalkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-aryl,O—CO—(C₁-C₆)-heterocycle;

PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂,S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-aryl, S—(CH₂)_(n)-heterocycle,SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-aryl, SO—(CH₂)_(n)-heterocycle,SO₂—(C₁-C₆)-alkyl, SO₂—(CH₂)_(n)-aryl, SO₂—(CH₂)_(n)-heterocycle,SO₂—NH(CH₂)_(n)-aryl, SO₂—NH(CH₂)_(n)-heterocycle,SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-aryl,SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-heterocycle, SO₂—N((CH₂)_(n)-aryl)₂,SO₂—N((CH₂)_(n)-heterocycle)₂ where n may be 0-6 and the aryl radical orheterocyclic radical may be up to disubstituted by F, Cl, Br, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or NH₂;C(═NH)(NH₂), NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,NH—CO(C₁-C₆)-alkyl, NH—COO—(C₁-C₆)-alkyl, NH—CO-aryl, NH—CO-heterocycle,NH—COO-aryl, NH—COO-heterocycle, NH—CO—NH—(C₁-C₆)-alkyl, NH—CO—NH-aryl,NH—CO—NH-heterocycle, N((C₁-C₆)-alkyl)-CO—(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)-COO—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)-CO-aryl,N((C₁-C₆)-alkyl)-CO-heterocycle, N((C₁-C₆)-alkyl)-COO-aryl,N((C₁-C₆)-alkyl)-COO-heterocycle, N((C₁-C₆)-alkyl)-CO—NH—(C₁-C₆)-alkyl),N((C₁-C₆)-alkyl)-CO—NH-aryl, N((C₁-C₆)-alkyl)-CO—NH-heterocycle,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)₂,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-aryl,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-heterocycle,N((C₁-C₆)-alkyl)-CO—N-(aryl)₂, N((C₁-C₆)-alkyl)-CO—N-(heterocycle)₂,N(aryl)-CO—(C₁-C₆)-alkyl, N(heterocycle)-CO—(C₁-C₆)-alkyl,N(aryl)-COO—(C₁-C₆)-alkyl, N(heterocycle)-COO—(C₁-C₆)-alkyl,N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl,N(heterocycle)-COO-aryl, N(aryl)-CO—NH—(C₁-C₆)-alkyl),N(heterocycle)-CO—NH—(C₁-C₆)-alkyl), N(aryl)-CO—NH-aryl,N(heterocycle)-CO—NH-aryl, N(aryl)-CO—N((C₁-C₆)-alkyl)₂,N(heterocycle)-CO—N((C₁-C₆)-alkyl)₂, N(aryl)-CO—N((C₁-C₆)-alkyl)-aryl,N(heterocycle)-CO—N((C₁-C₆)-alkyl)-aryl, N(aryl)-CO—N-(aryl)₂,N(heterocycle)-CO—N-(aryl)₂, aryl, O—(CH₂)_(n)-aryl andO—(CH₂)_(n)-heterocycle, where n may be 0-6, where the aryl radical orheterocyclic radical may be mono- to trisubstituted by F, Cl, Br, I, OH,CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl orCONH₂.

An aryl group for the purposes of this application is a phenyl,naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonyl,indanyl or indan-1-onyl radical.

The aryl radicals may be mono- or polysubstituted by suitable groups,for example:

F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, cycloalkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-aryl,O—CO—(C₁-C₆)-heterocycle;

PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂,S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-aryl, S—(CH₂)_(n)-heterocycle,SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-aryl, SO—(CH₂)_(n)-heterocycle,SO₂—(C₁-C₆)-alkyl, SO₂—(CH₂)_(n)-aryl, SO₂—(CH₂)_(n)-heterocycle,SO₂—NH(CH₂)_(n)-aryl, SO₂—NH(CH₂)_(n)-heterocycle,SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-aryl,SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-heterocycle, SO₂—N((CH₂)_(n)-aryl)₂,SO₂—N((CH₂)_(n)-heterocycle)₂ where n may be 0-6 and the aryl radical orheterocyclic radical may be up to disubstituted by F, Cl, Br, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or NH₂;C(═NH)(NH₂), NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,NH—CO—(C₁-C₆)-alkyl, NH—COO—(C₁-C₆)-alkyl, NH—CO-aryl,NH—CO-heterocycle, NH—COO-aryl, NH—COO-heterocycle,NH—CO—NH—(C₁-C₆)-alkyl, NH—CO—NH-aryl, NH—CO—NH-heterocycle,N((C₁-C₆)-alkyl)-CO—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)-COO—(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)-CO-aryl, N((C₁-C₆)-alkyl)-CO-heterocycle,N((C₁-C₆)-alkyl)-COO-aryl, N((C₁-C₆)-alkyl)-COO-heterocycle,N((C₁-C₆)-alkyl)-CO—NH—(C₁-C₆)-alkyl), N((C₁-C₆)-alkyl)-CO—NH-aryl,N((C₁-C₆)-alkyl)-CO—NH-heterocycle,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)₂,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-aryl,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-heterocycle,N((C₁-C₆)-alkyl)-CO—N-(aryl)₂, N((C₁-C₆)-alkyl)-CO—N-(heterocycle)₂,N(aryl)-CO—(C₁-C₆)-alkyl, N(heterocycle)-CO—(C₁-C₆)-alkyl,N(aryl)-COO—(C₁-C₆)-alkyl, N(heterocycle)-COO—(C₁-C₆)-alkyl,N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl,N(heterocycle)-COO-aryl, N(aryl)-CO—NH—(C₁-C₆)-alkyl),N(heterocycle)-CO—NH—(C₁-C₆)-alkyl), N(aryl)-CO—NH-aryl,N(heterocycle)-CO—NH-aryl, N(aryl)-CO—N((C₁-C₆)-alkyl)₂,N(heterocycle)-CO—N((C₁-C₆)-alkyl)₂, N(aryl)-CO—N((C₁-C₆)-alkyl)-aryl,N(heterocycle)-CO—N((C₁-C₆)-alkyl)-aryl, N(aryl)-CO—N-(aryl)₂,N(heterocycle)-CO—N-(aryl)₂, aryl, O—(CH₂)_(n)-aryl andO—(CH₂)_(n)-heterocycle, where n may be 0-6, where the aryl substituentor heterocyclic group may be mono- to trisubstituted by F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl orCONH₂.

A cycloalkyl group for the purposes of this application is a ring systemwhich comprises one or more rings and is present in saturated orpartially unsaturated form (with one or two double bonds), and is formedexclusively from carbon atoms, for example cyclopropyl, cyclopentyl,cyclopentenyl, cyclohexyl or adamantyl.

The cycloalkyl groups may be mono- or polysubstituted by suitablegroups, for example:

F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, cycloalkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-aryl,O—CO—(C₁-C₆)-heterocycle;

PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂,S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-aryl, S—(CH₂)_(n)-heterocycle,SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-aryl, SO—(CH₂)_(n)-heterocycle,SO₂—(C₁-C₆)-alkyl, SO₂—(CH₂)_(n)-aryl, SO₂—(CH₂)_(n)-heterocycle,SO₂—NH(CH₂)_(n)-aryl, SO₂—NH(CH₂)_(n)-heterocycle,SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-aryl,SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-heterocycle, SO₂—N((CH₂)_(n)-aryl)₂,SO₂—N((CH₂)_(n)-heterocycle)₂ where n may be 0-6 and the aryl radical orheterocyclic radical may be up to disubstituted by F, Cl, Br, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or NH₂; C(═NH)(NH₂), NH₂,NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NH—CO—(C₁-C₆)-alkyl,NH—COO—(C₁-C₆)-alkyl, NH—CO-aryl, NH—CO-heterocycle, NH—COO-aryl,NH—COO-heterocycle, NH—CO—NH—(C₁-C₆)-alkyl, NH—CO—NH-aryl,NH—CO—NH-heterocycle, N((C₁-C₆)-alkyl)-CO—(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)-COO—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)-CO-aryl,N((C₁-C₆)-alkyl)-CO-heterocycle, N((C₁-C₆)-alkyl)-COO-aryl,N((C₁-C₆)-alkyl)-COO-heterocycle, N((C₁-C₆)-alkyl)-CO—NH—(C₁-C₆)-alkyl),N((C₁-C₆)-alkyl)-CO—NH-aryl, N((C₁-C₆)-alkyl)-CO—NH-heterocycle,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)₂,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-aryl,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-heterocycle,N((C₁-C₆)-alkyl)-CO—N-(aryl)₂, N((C₁-C₆)-alkyl)-CO—N-(heterocycle)₂,N(aryl)-CO—(C₁-C₆)-alkyl, N(heterocycle)-CO—(C₁-C₆)-alkyl,N(aryl)-COO—(C₁-C₆)-alkyl, N(heterocycle)-COO—(C₁-C₆)-alkyl,N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl,N(heterocycle)-COO-aryl, N(aryl)-CO—NH—(C₁-C₆)-alkyl),N(heterocycle)-CO—NH—(C₁-C₆)-alkyl), N(aryl)-CO—NH-aryl,N(heterocycle)-CO—NH-aryl, N(aryl)-CO—N((C₁-C₆)-alkyl)₂,N(heterocycle)-CO—N((C₁-C₆)-alkyl)₂, N(aryl)-CO—N((C₁-C₆)-alkyl)-aryl,N(heterocycle)-CO—N((C₁-C₆)-alkyl)-aryl, N(aryl)-CO—N-(aryl)₂,N(heterocycle)-CO—N-(aryl)₂, aryl, O—(CH₂)_(n)-aryl andO—(CH₂)_(n)-heterocycle, where n may be 0-6, where the aryl radical orheterocyclic radical may be mono- to trisubstituted by F, Cl, Br, I, OH,CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl orCONH₂.

The terms heterocycle, heterocycle and heterocyclic groups for thepurposes of this application are rings and ring systems which, apartfrom carbon, also contain heteroatoms, for example nitrogen, oxygen orsulfur. This definition also includes ring systems in which theheterocycle or the heterocyclic radical is fused to benzene rings. Theheterocycle or the heterocyclic radical may be aromatic, saturatedaliphatic or partially unsaturated aliphatic.

Suitable heterocycle radicals or “heterocyclic radicals” are acridinyl,azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl,4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthenyl.

Pyridyl is 2-, 3- or 4-pyridyl. Thienyl is 2- or 3-thienyl. Furyl is 2-or 3-furyl.

Also included are the corresponding N-oxides of these compounds, i.e.,for example, 1-oxy-2-, -3- or -4-pyridyl.

Also included are the mono- or polybenzofused derivatives of theseheterocycles.

The heterocyclic rings or heterocyclic radicals may be mono- orpolysubstituted by suitable groups, for example: F, Cl, Br, I, CF₃, NO₂,N₃, CN, COOH, COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₆)alkyl,CON[(C₁-C₆)alkyl]₂, cycloalkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-aryl,O—CO—(C₁-C₆)-heterocycle;

PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂,S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-aryl, S—(CH₂)_(n)-heterocycle,SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-aryl, SO—(CH₂)_(n)-heterocycle,SO₂—(C₁-C₆)-alkyl, SO₂—(CH₂)_(n)-aryl, SO₂—(CH₂)_(n)-heterocycle,SO₂—NH(CH₂)_(n)-aryl, SO₂—NH(CH₂)_(n)-heterocycle,SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-aryl,SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-heterocycle, SO₂—N((CH₂)_(n)-aryl)₂,SO₂—N((CH₂)_(n)-heterocycle)₂ where n may be 0-6 and the aryl radical orheterocyclic radical may be up to disubstituted by F, Cl, Br, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or NH₂;C(═NH)(NH₂), NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,NH—CO—(C₁-C₆)-alkyl, NH—COO—(C₁-C₆)-alkyl, NH—CO-aryl,NH—CO-heterocycle, NH—COO-aryl, NH—COO-heterocycle,NH—CO—NH—(C₁-C₆)-alkyl, NH—CO—NH-aryl, NH—CO—NH-heterocycle,N((C₁-C₆)-alkyl)-CO—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)-COO—(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)-CO-aryl, N((C₁-C₆)-alkyl)-CO-heterocycle,N((C₁-C₆)-alkyl)-COO-aryl, N((C₁-C₆)-alkyl)-COO-heterocycle,N((C₁-C₆)-alkyl)-CO—NH—(C₁-C₆)-alkyl), N((C₁-C₆)-alkyl)-CO—NH-aryl,N((C₁-C₆)-alkyl)-CO—NH-heterocycle,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)₂,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-aryl,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-heterocycle,N((C₁-C₆)-alkyl)-CO—N-(aryl)₂, N((C₁-C₆)-alkyl)-CO—N-(heterocycle)₂,N(aryl)-CO—(C₁-C₆)-alkyl, N(heterocycle)-CO—(C₁-C₆)-alkyl,N(aryl)-COO—(C₁-C₆)-alkyl, N(heterocycle)-COO—(C₁-C₆)-alkyl,N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl,N(heterocycle)-COO-aryl, N(aryl)-CO—NH—(C₁-C₆)-alkyl),N(heterocycle)-CO—NH—(C₁-C₆)-alkyl), N(aryl)-CO—NH-aryl,N(heterocycle)-CO—NH-aryl, N(aryl)-CO—N((C₁-C₆)-alkyl)₂,N(heterocycle)-CO—N((C₁-C₆)-alkyl)₂, N(aryl)-CO—N((C₁-C₆)-alkyl)-aryl,N(heterocycle)-CO—N((C₁-C₆)-alkyl)-aryl, N(aryl)-CO—N-(aryl)₂,N(heterocycle)-CO—N-(aryl)₂, aryl, O—(CH₂)_(r)-aryl andO—(CH₂)_(n)-heterocycle, where n may be 0-6, where the aryl radical orheterocyclic radical may be mono- to trisubstituted by F, Cl, Br, I, OH,CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl orCONH₂.

The compound(s) of the present invention according to formula (I) mayalso be administered in combination with additional active ingredients.

The amount of a compound of the present invention as defined by formulaI that is required to achieve the desired biological effect is dependentupon a series of factors, for example, the specific compound selected,the intended use, the mode of administration and the clinical conditionof the patient. The daily dose is generally in the range from 0.3 mg to100 mg (typically from 3 mg to 50 mg) per day per kilogram ofbodyweight, for example 3-10 mg/kg/day. An intravenous dose may, forexample, be in the range from 0.3 mg to 1.0 mg/kg and may suitably beadministered as an infusion of from 10 ng to 100 ng per kilogram perminute. Suitable infusion solutions for these purposes may, for example,contain from 0.1 ng to 10 ng, typically from 1 ng to 10 mg, permilliliter. Single doses may contain, for example, from 1 mg to 10 g ofthe active ingredient. Ampoules for injections may therefore contain,for example, from 1 mg to 100 mg, and single dose formulations which canbe administered orally, for example tablets or capsules, may contain,for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.

The compounds of the formula I may be used for therapy of theabove-mentioned conditions as the compounds themselves, although theyare preferably in the form of a pharmaceutical composition with apharmaceutically acceptable carrier. The carrier of course has to bepharmaceutically acceptable in the sense that it is compatible with theother constituents of the composition and is not detrimental to thehealth of the patient. The carrier may be a solid or a liquid or bothand is preferably formulated with the compound as a single dose, forexample as a tablet, which may contain from 0.05 to 95% by weight of theactive ingredient. Further pharmaceutically active substances maylikewise be present, including further compounds of the formula I. Theinventive pharmaceutical compositions may be produced by one of theknown pharmaceutical methods which consist essentially in mixing theconstituents with pharmacologically acceptable carriers and/orexcipients.

Inventive pharmaceutical compositions are those which are suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(for example subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the type of the compound of the formula Iused in each case. Coated formulations and coated slow-releaseformulations are also encompassed by the scope of the invention.Preference is given to acid- and gastric fluid-resistant formulations.Suitable gastric fluid-resistant coatings include cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical preparations for oral administration may be inthe form of separate units, for example capsules, cachets, lozenges ortablets, each of which contains a certain amount of the compound of theformula I; as powder or granules; as solution or suspension in anaqueous or nonaqueous liquid; or as an oil-in-water or water-in-oilemulsion. These compositions may, as already mentioned, be prepared byany suitable pharmaceutical method which includes a step in which theactive ingredient and the carrier (which may consist of one or moreadditional constituents) are brought into contact. In general, thecompositions are prepared by uniform and homogeneous mixing of theactive ingredient with a liquid carrier and/or finely divided solidcarrier, after which the product is shaped if necessary. For example, atablet can thus be produced by compressing or shaping a powder orgranules of the compound, optionally with one or more additionalconstituents. Compressed tablets can be prepared by tableting thecompound in free-flowing form, for example a powder or granules,optionally mixed with a binder, lubricant, inert diluent and/or one (ormore) surfactants/dispersants in a suitable machine. Shaped tablets canbe prepared by shaping the pulverulent compound moistened with an inertliquid diluent in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration include lozenges which contain a compound of the formulaI with a flavoring, customarily sucrose, and gum arabic or tragacanth,and pastilles which include the compound in an inert base, such asgelatin and glycerol or sucrose and gum arabic.

Suitable pharmaceutical compositions for parenteral administrationinclude preferably sterile aqueous preparations of a compound of theformula I which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although the administration may also be subcutaneous, intramuscular orintradermal as an injection. These preparations can preferably beproduced by mixing the compound with water and making the solutionobtained sterile and isotonic with the blood. Injectable compositionsaccording to the invention generally contain from 0.1 to 5% by weight ofthe active compound.

Suitable pharmaceutical compositions for rectal administration arepreferably in the form of single dose suppositories. These can beprepared by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Suitable pharmaceutical compositions for topical application on the skinare preferably in the form of an ointment, cream, lotion, paste, spray,aerosol or oil. Useful carriers include petroleum jelly, lanolin,polyethylene glycols, alcohols and combinations of two or more of thesesubstances. The active ingredient is generally present in aconcentration of from 0.1 to 15% by weight of the composition,preferably from 0.5 to 2%.

Transdermal administration is also possible. Suitable pharmaceuticalcompositions for transdermal applications may be in the form of singleplasters which are suitable for long-term close contact with theepidermis of the patient. Such plasters suitably contain the activeingredient in an optionally buffered aqueous solution, dissolved and/ordispersed in an adhesive or dispersed in a polymer. A suitable activeingredient concentration is from approx. 1% to 35%, preferably fromapprox. 3% to 15%. A particular means of releasing the active ingredientmay be by electrotransport or iontophoresis, as described, for example,in Pharmaceutical Research, 2(6): 318 (1986).

The compounds of the formula I may be administered alone or else also incombination with further active ingredients. Further useful activeingredients for combination products are as follows:

All antidiabetics mentioned in the Rote Liste 2001, chapter 12. They canbe combined with the inventive compounds of the formula I, in particularfor synergistic enhancement of action. The active ingredient combinationcan be administered either by separately administering the activeingredients to the patient or in the form of combination products inwhich a plurality of active ingredients are present in onepharmaceutical preparation. Most of the active ingredients listedhereinbelow are disclosed in USP Dictionary of USAN and InternationalDrug Names, US Pharmacopeia, Rockville 2001.

Antidiabetics include insulin and insulin derivatives, for exampleLantus® (see www.lantus.com) or Apidra®, fast-acting insulins (see U.S.Pat. No. 6,221,633), GLP-1 derivatives, for example those disclosed inWO 98/08871 of Novo Nordisk A/S, and orally active hypoglycemic activeingredients.

The orally active hypoglycemic active ingredients preferably includesulfonylureas, biguanidines, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1agonists, potassium channel openers, for example those disclosed in WO97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers,inhibitors of liver enzymes which are involved in the stimulation ofgluconeogenesis and/or glycogenolysis, modulators of glucose uptake,compounds which alter lipid metabolism such as antihyperlipidemic activeingredients and antilipidemic active ingredients, compounds which reducefood intake, PPAR and PXR agonists and active ingredients which act onthe ATP-dependent potassium channel of the beta cells (PPAR=peroxisomeproliferator-activated receptor, PXR=pregnane X receptor, ATP=adenosinetriphosphate).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an HMG-CoA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin (HMG-CoA=3-hydroxy-3-methylglutaryl coenzymeA).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a cholesterol absorption inhibitor, forexample, ezetimibe, tiqueside, pamaqueside, or with a compound asdescribed in PCT/EP 2004/00269, WO 2004/000804, WO 2004/000803, WO2004/000805, EP 0114531, U.S. Pat. No. 6,498,156.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a PPAR gamma agonist, for example,rosiglitazone, pioglitazone, JTT-501, GI 262570.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with PPAR alpha agonist, for example, GW9578, GW 7647.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a mixed PPAR alpha/gamma agonist, forexample, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in WO00/64888, WO 00/64876, DE10142734.4.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a fibrate, for example fenofibrate,clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an MTP inhibitor, for exampleimplitapide, BMS-201038 or R-103757 (MTP=microsomal triglyceridetransfer protein).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with bile acid absorption inhibitor (see,for example, U.S. Pat. No. 6,245,744 or U.S. Pat. No. 6,221,897), forexample HMR 1741.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a CETP inhibitor, for example JTT-705(CETP=cholesteryl ester transfer protein).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a polymeric bile acid adsorber, forexample cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an LDL receptor inducer (see U.S. Pat.No. 6,342,512), for example HMR1171, HMR1586 (LDL=low density lipids).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ACAT inhibitor, for exampleavasimibe (ACAT=acyl-coenzyme A:cholesterol acyl transferase).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an antioxidant, for example OPC-14117.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein lipase inhibitor, forexample NO-1886.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ATP citrate lyase inhibitor, forexample SB-204990.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a squalene synthetase inhibitor, forexample BMS-188494.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein(a) antagonist, forexample CI-1027 or nicotinic acid.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipase inhibitor, for exampleorlistat.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with insulin.

In one embodiment, the compounds of the formula I are administered incombination with a sulfonylurea, for example tolbutamide, glibenclamide,glipizide or glimepiride.

In one embodiment, the compounds of the formula I are administered incombination with a biguanide, for example metformin.

In yet another embodiment, the compounds of the formula I areadministered in combination with a meglitinide, for example repaglinide.

In one embodiment, the compounds of the formula I are administered incombination with a thiazolidinedione, for example troglitazone,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed inWO 97/41097 of Dr. Reddy's Research Foundation, in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]-phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment, the compounds of the formula I are administered incombination with an α-glucosidase inhibitor, for example miglitol oracarbose.

In one embodiment, the compounds of the formula I are administered incombination with adenosine A1 agonists, for example those which aredescribed in WO 2004/003002.

In one embodiment, the compounds of the formula I are administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, for example tolbutamide,glibenclamide, glipizide, glimepiride or repaglinide. In one embodiment,the compounds of the formula I are administered in combination with morethan one of the abovementioned compounds, for example in combinationwith a sulfonylurea and metformin, a sulfonylurea and acarbose,repaglinide and metformin, insulin and a sulfonylurea, insulin andmetformin, insulin and troglitazone, insulin and lovastatin, etc.

In a further embodiment, the compounds of the formula I are administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A, et al., M.: Hormone and Metabolic Research (2001),33(9), 554-558), NPY antagonists (NPY=neuropeptide Y, e.g.naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amidehydrochloride (CGP 71683A)), MC4 agonists (MC4=melanocortin 4 receptor,e.g. 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxo-ethyl]amide;(WO 01/91752)), orexin antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea; hydrochloride(SB-334867-A)), H3 agonists (H3=histamine receptor, e.g.3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208)); TNF agonists (TNF=tumor necrosisfactor), CRF antagonists (CRF=corticotropin releasing factor, e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585)), CRF BP antagonists (CRF BP=corticotropin releasingfactor binding protein, e.g. urocortin), urocortin agonists, β3 agonists(e.g.1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanolhydrochloride (WO 01/83451)), CB1 (cannabinoid receptor 1) receptorantagonists (e.g. rimonabant or the active ingredients specified in WO02/28346), MSH (melanocyte-stimulating hormone) agonists, CCK-A(CCK-A=cholecystokinin-A) agonists (e.g.{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptakeinhibitors (e.g. dexfenfluramine), mixed serotoninergic andnoradrenergic compounds (e.g. WO 00/71549), 5HT agonists (serotoninmimetics), e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt(WO 01/09111), bombesin agonists, galanin antagonists, growth hormone(e.g. human growth hormone), growth hormone-releasing compounds(6-benzyloxy-1-(2-diisopropylaminoethyl-carbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (WO 01/85695)), TRH agonists (TRH=TSH releasinghormone; TSH=thyroid-stimulating hormone; thyrotropin), see, forexample, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptinagonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.;Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as apotential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881), DA agonists (DA dopamine autoreceptor, forexample bromocriptine, doprexin), lipase/amylase inhibitors (e.g., WO00/40569), PPAR modulators (e.g., WO 00/78312), RXR (RXR=retinoid Xreceptor) modulators or TR-β agonists.

In one embodiment of the invention, the other active ingredient isleptin; see, for example, “Perspectives in the therapeutic use ofleptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, ExpertOpinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In one embodiment, the other active ingredient is dexamphetamine oramphetamine.

In one embodiment, the other active ingredient is fenfluramine ordexfenfluramine.

In yet another embodiment, the other active ingredient is sibutramine.

In one embodiment, the other active ingredient is orlistat.

In one embodiment, the other active ingredient is mazindol orphentermine.

In another embodiment, the other active ingredient is rimonabant.

In one embodiment, the compounds of the formula I are administered incombination with dietary fiber materials, preferably insoluble dietaryfiber materials (see, for example, Carob/Caromax® (Zunft H J; et al.,Carob pulp preparation for treatment of hypercholesterolemia, ADVANCESIN THERAPY (2001 September-October), 18(5), 230-6.); Caromax is acarob-containing product supplied by Nutrinova, Nutrition Specialties &Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt/Main)).Combination with Caromax® is possible in one preparation or by separateadministration of compounds of the formula I and Caromax®. Caromax® canalso be administered in the form of foodstuffs, for example, in bakeryproducts or muesli bars.

The aforementioned compounds and those listed below are useful in thepreparation of combination formulations together with those disclosedand claimed herein. Any suitable combination of the compounds accordingto the invention with one or more of these compounds and optionally oneor more further pharmacologically active substances is regarded as beingcovered by the scope of protection of the present invention as definedby the claims that follow herein.

The compounds of the formula I can be prepared by reacting suitablestarting materials of the formula II in which X is a leaving group, suchas chlorine, bromine, iodine, sulfonyloxy, sulfinyl or sulfoxyl, and R30is defined as CO—R21 or a protective group for amines, with a compoundof the formula IV optionally in the presence of suitable bases and insuitable solvents.

In the cases where R4 and R5 are both hydrogen, it may be appropriate touse the radical IV in a form protected on the nitrogen function and todetach the protecting group again on completion of reaction with 11.Such suitable protecting groups and the processes for their introductionand detachment are known (see: Theodora W. Greene and Peter G. M. Wuts,Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons,Inc., New York, 1999).

The halogen compounds of the formula II can be obtained by knownprocesses, for example by halogenating the corresponding H, hydroxyl orthio compound (formula II, X═H, OH or SH). Suitable halogenating agentsmay, by way of example, be halogens such as chlorine and bromine,N-bromosuccinimide, phosphorus pentachloride or phosphorus oxychloride.

The synthesis of compounds of formula II is well known and described inthe literature. They may be prepared, for example, by condensingsubstituted diaminobenzene derivatives with aldehydes in the presence ofan oxidizing agent (for example atmospheric oxygen, oxygen, iodine,oxone, quinones, peroxides, etc.), or alternatively with carboxylicacids, nitrites or amides, without or in the presence of a catalyst. Theconversion of the NR30 radical to the NR20-CO—R21 radicals is describedin the literature.

Some derivatives of the formula IV, for example piperidin-3-ylamides,are commercially available.

The tabulated examples listed below are provided to better illustratemethods for practicing the present invention as disclosed herein. Theexamples are provided to better describe and more specifically set forththe compounds, processes and methods of the present invention ascontemplated herein. However, it is to be recognized that they are forillustrative purposes only, and should not be interpreted as limitingthe spirit and scope of the invention as later recited by the claimsthat follow.

TABLE 1 I

bonding site Ex. N(R20)—(C═O)—R21 R20 R21 R3 NR4R5 n R11 1 6 H Phenyl-—CH₂—CH═C(CH₃)₂ 3-R—NH₂ × 0 — TFA 2 6 H Benzyl- —CH₂—CH═C(CH₃)₂ 3-R—NH₂× 0 — TFA 3 6 H 4-Cl-Benzyl- —CH₂—CH═C(CH₃)₂ 3-R—NH₂ × 0 — TFA 4 6 H3-CF₃-Benzyl- —CH₂—CH═C(CH₃)₂ 3-R—NH₂ × 0 — TFA 5 5 H Phenyl-—CH₂—CH═C(CH₃)₂ 3-R—NH₂ × 0 — TFA

The compounds of the formula I feature favorable effects on lipid andcarbohydrate metabolism; in particular, they lower the blood sugar leveland are suitable for the treatment of type II diabetes, of insulinresistance, of dislipidemias and of metabolic syndrome/syndrome X.Moreover, the compounds are suitable for the treatment and prophylaxisof arteriosclerotic manifestations. The compounds can be used alone orin combination with further blood sugar-lowering active ingredients. Thecompounds act as DPP IV (dipeptidyl peptidase IV) inhibitors and arealso suitable for the treatment of disorders of perception and otherpsychiatric indications, for example depressions, anxiety states,anxiety neuroses, schizophrenia, and for the treatment of disordersassociated with the circadian rhythm, for weight reduction in mammals,for the treatment of immune disorders and for the treatment of drugabuse.

They are additionally suitable for the treatment of cancer, arthritis,osteoarthritis, osteoporosis, sleep disorders, sleep apnea, masculineand feminine sexual disorders, inflammations, acne, pigmentation of theskin, disorders of steroid metabolism, skin diseases, psoriasis,mycoses, neurodegenerative disorders, multiple sclerosis and Alzheimer'sdisease.

The efficacy of the compounds was tested as follows:

Measurement of the DPP-IV Activity:

Material:

DPP-IV from porcine kidneys (Sigma, Munich)

H-Ala-Pro-AFC (Bachem, Weil am Rhein)

Test Conditions:

DPP-IV (1 mU/ml, end concentration)

H-Ala-Pro-AFC (15 μm end concentration)

in Tris/HCl (40 mM, pH 7.4), total volume 0.2 ml

The reaction was performed at room temperature for different periods(typically 10 minutes) and stopped at the end of the reaction by adding20 μl of ZnCl₂ (1 M). The conversion of H-Ala-Pro-AFC was determinedfluorimetrically by measuring the emission at 535 nm on excitation at405 nm. In the case of addition of inhibitors, the buffer volume addedwas adjusted such that a total volume of the test mixture of 200 μlmaintained.

% inhibition at a fixed concentration was calculated as follows:(1-enzyme activity_(inhibited reaction)/enzymeactivity_(uninhibited reaction))×100

IC₅₀ values for inhibitors were determined by varying the inhibitorconcentrations in the case of the specified substrate concentration of15 μM. K_(i) and K_(m) values were determined by corresponding variationof substrate and inhibitor concentration as described (Dixon, M. andWebb, E. C. (1979) Enzymes, third edition, pp. 47-206, Academic Press).The values for K_(m), IC₅₀ and K_(i) were calculated using acommercially available software package (Leatherbarrow, R. J. (1992)GraFit Version 3.0, Erithacus Software Ltd. Staines, U.K.).

TABLE 2 Biological activity of the examples: IC50 [μm] % inhibitionExample at 30 μm 1 2.5 2 2.7 3 78 4 43

It can be seen from the table that the compounds of the formula Iinhibit the activity of the DPP-IV (dipeptidyl peptidase IV) and arethus very suitable for lowering the blood sugar level.

The preparation of a working example will be described in detailhereinafter; the other compounds of the formula I were obtainedanalogously:

Example 1R—N-[2-(3-Aminopiperidin-1-yl)-1-(3-methylbut-2-enyl)-1H-benzimidazol-6-yl]-benzamidetrifluoroacetic acid salt a) 2-Bromo-5/6-nitro-1H-benzimidazole

A suspension of 5.0 g (25.61 mmol) of 5/6-nitro-1H-benzimidazole-2-thiolin 30 ml of methanol and 10 ml of hydrogen bromide (48% in water) wascooled to 5-10° C. and admixed with 3.55 g (22.2 mmol) of bromine.Subsequently, the mixture was stirred at 5-10° C. for 45 minutes andadmixed with 8 ml of methanol/aqueous NH₃ solution=3/1. The precipitatewas filtered off with suction, and the mother liquor was poured onto icewater. This formed another precipitate which was likewise filtered offwith suction. The combined precipitates were partitioned between ethylacetate and water, dried and concentrated under reduced pressure. 1.12 gof the desired product were obtained and were used in the next stagewithout further purification.

b) 2-Bromo-1-(3-methylbut-2-enyl)-5/6-nitro-1H-benzimidazole

0.55 g (2.27 mmol) of 2-bromo-5/6-nitro-1H-benzimidazole was dissolvedin 10 ml of dimethylformamide, admixed with 11.1 g (3.41 mmol) of cesiumcarbonate and stirred at room temperature for 30 minutes. 408 mg (2.50mmol) of 1-bromo-3-methyl-2-butene was added and the reaction mixturewas stirred at room temperature for 4 hours. The precipitate wasfiltered off with suction and washed with dimethylformamide. Thefiltrate was concentrated under reduced pressure and the residue waspartitioned between ethyl acetate and water. The organic phase was driedand concentrated under reduced pressure. 371 mg (53%) of the desiredproduct were obtained.

LC-MS: m/z=310.0/312.0 (M+H)⁺.

c) tert-ButylR-{1-[1-(3-methylbut-2-enyl)-6-nitro-1H-benzimidazol-2-yl]piperidin-3-yl}carbamate

260 mg (1.29 mmol) of tert-butyl R-piperidin-3-yl carbamate weredissolved in 2 ml of dimethylformamide and admixed with 575 mg (1.77mmol) of cesium carbonate, and stirred at room temperature for 30minutes. 365 mg (1.18 mmol) of2-bromo-1-(3-methylbut-2-enyl)-5/6-nitro-1H-benzimidazole were dissolvedin 8 ml of dimethylformamide and added slowly. The reaction mixture wasstirred at 40° C. for 6 hours. The precipitate was filtered off withsuction and washed with dimethylformamide. The filtrate was concentratedand partitioned between ethyl acetate and water. The organic phase wasdried and concentrated under reduced pressure. The crude mixture wasseparated on silica gel (eluent: heptane/ethyl acetate, gradient: 3/1 to1/1). 176 mg (35%) of tert-butylR-{1-[1-(3-methylbut-2-enyl)-5-nitro-1H-benzimidazol-2-yl]piperidin-3-yl}carbamate and 163 mg (32%) of the desired product were obtained.

LC-MS: m/z=430.2 (M+H)⁺.

d) tert-ButylR-{1-[6-amino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-yl]piperidin-3-yl}carbamate

A solution of 163 mg (0.38 mmol) of tert-butylR-{1-[1-(3-methylbut-2-enyl)-6-nitro-1H-benzimidazol-2-yl]piperidin-3-yl}carbamate in 10 ml of ethanol was added dropwise to a suspension of 106mg (1.90 mmol) of iron and 18 mg (0.34 mmol) of ammonium chloride in 1ml of water, and the mixture was boiled at reflux for 3 hours. Thecatalyst was filtered off and washed with ethanol. The filtrate wasconcentrated under reduced pressure. 155 mg of the desired product wereobtained and were reacted in the next stage without furtherpurification.

e) tert-ButylR-{1-[6-benzoylamino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-yl]piperidin-3-yl}carbamate

20 mg (0.06 mmol) of cesium carbonate were added to a solution of 50 mg(0.13 mmol) of tert butylR-{1-[6-amino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-yl]piperidin-3-yl}carbamate in 5 ml of dimethylformamide, and the mixture was stirred atroom temperature for 30 minutes. Subsequently, 18 mg (0.13 mmol) ofbenzoyl chloride were added and the mixture was stirred at roomtemperature for 24 hours. The reaction mixture was extracted withdichloromethane and water and the organic phase was dried andconcentrated under reduced pressure. The residue was separated on silicagel (eluent: heptane/ethyl acetate, gradient: 1/1 to 0/1). 24 mg (38%)of the desired compound were obtained.

MS: m/z=503.3 (M+H)⁺.

f)R—N-[2-(3-Aminopiperidin-1-yl)-1-(3-methylbut-2-enyl)-1H-benzimidazol-6-yl]-benzamidetrifluoroacetic acid salt (A003407940A)

24 mg (0.05 mmol) of tert-butylR-{1-[6-benzoylamino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-ylpiperidin-3-yl}carbamate were reacted with 80 μl of trifluoroacetic acid/water mixture(10 to 1) at room temperature for 16 hours to give the desired productin quantitative yield.

MS: m/z=404.2 (M+H)⁺.

What is claimed is:
 1. The compound of formula I

wherein R20 is H; R21 is selected from the group consisting of(C₆-C₁₀)-aryl and (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, where the arylradicals may be mono- or polysubstituted by F, Cl, Br, I, CN, NO₂, SH,OH, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, or S—(C₁-C₆)-alkyl; R3 is(C₂-C₁₀)-alkenyl; R4, R5 are each H; R11 is selected from the groupconsisting of F, Cl, Br, I, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, NH₂,NH(C₁-C₆)-alkyl, NH(C₃-C₇)-cycloalkyl, N((C₁-C₆)-alkyl)₂ andO—(C₁-C₆)-alkyl, where the alkyl groups may be mono- or polysubstitutedby F, Cl, Br or I; and n is 0; or a pharmaceutically acceptable saltthereof.
 2. A pharmaceutical composition comprising the compound offormula I as recited in claim 1 further combined with one or moreadditional solvents, bulking agents, binders, lubricants, inert diluentsand/or one (or more) surfactants/dispersants, excipients, thickeningagents, buffers, polymers, stabilizers, binders, flavorants, sweetenersformulated as a pharmaceutical composition for administration as atablet, capsule, intravenous solution, transdermal gel, powder, oralsolution, syrup, intranasal spray, or lozenge to a patient in needthereof.